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Biosimilar mAbs – a unique and distinct market (for the time being…?)

Biologic therapies are complex, high molecular weight protein-based therapeutics that are manufactured by living organisms. These differ from ‘traditional’ low molecular weight compounds that have been created by chemical synthesis. When low molecular weight medicines lose patent protection, other companies can produce generic versions, which are exact copies of this innovator compound. By contrast, due to their much greater structural and manufacturing complexity, making exact ‘generic’ copies of biologics is virtually impossible. However, what compounds can be produced are termed ‘biosimilars’, biological products that are similar to and have comparable structure and efficacy to a branded reference biological product.

Why are biosimilars receiving so much attention?

Biosimilar versions of various molecules including epoetins, insulins, somatropins, growth hormones, and follitropins have existed for several years in many markets. Recently, interest in biosimilars has exploded with the advent of biosimilar monoclonal antibodies (mAbs). Biologic mAbs represent many of the best-selling, high-cost medicines and as such provide an opportunity for significant payer savings. The Food and Drug Administration (FDA) and European Commission approved their first biosimilar mAbs in 2016 and 2013, respectively, and have approved a total of three and six biosimilars, respectively, as of May 2017.

How do biosimilars receive regulatory approval?

Biosimilars are treated by regulators in a distinct manner, requiring less supportive data for approval than reference biologics (which typically require a full preclinical program and Phase 3 studies in all targeted indications) but more than generic products (where a bioequivalence study forms the key clinical data and no pre-clinical testing is required). Biosimilars require an abbreviated pre-clinical program alongside comparative pharmacokinetic and pharmacodynamic Phase 1 studies and Phase 3 clinical studies. However, a Phase 3 study is not required in all indications, as the marketing authorization may be extrapolated from the first to all subsequent reference product indications.

Once biosimilars are on the market, how are they priced, purchased, and prescribed?

Discounting is obviously a key driver for biosimilar adoption. However, discounts on biosimilar products are typically more limited than discounts on generics due the higher costs of manufacturing, clinical development, and marketing. Typically, generic drugs are deemed interchangeable with the branded originator product and substitution is automatic. By contrast, the decision to use a biosimilar involves multiple stakeholders, and appropriate initiatives must be present to incentivize stakeholders at different decision-making points (Figure 1).

When a biosimilar receives marketing authorization it can be prescribed by physicians. However, it does not address the key question as to whether a biosimilar may be considered ‘substitutable’ (when a pharmacist can replace the originator biologic with the biosimilar with physician’s consent) or ‘interchangeable’ (when a pharmacist can substitute the biosimilar without physician’s consent, typical of generic products) with its reference biologic.

In the US, the FDA can designate a biosimilar interchangeable, via a process that is more rigorous than that for standard (substitutable) biosimilar approval and which requires additional data. No biosimilar has attained interchangeable status to date. By contrast, in Europe, the European Medicines Agency does not have the authority to designate biosimilars as interchangeable – this rests with the individual member states. In some counties, such as France or Spain, biosimilars are treated akin to innovator products with no interchangeability permitted, whereas in others, such as Germany, they more like generics with automatic substitution encouraged. This variation in treating biosimilars as innovator products or generics also extends to other key domains (Table 1). Some markets (e.g., Germany) have tendering processes for biosimilars (in the same way that they contract generics). Other markets (e.g., France) require biosimilars to be appraised by their Health Technology Assessment body in the same way as a new therapeutic agent, whereas still others (e.g., England) require no appraisal, as in the case of generics. Overall, many markets fall between the two ends of the market access spectrum of being treated ‘like generics’ versus ‘like biologics’ (Figure 2).

It is clear that that the more experienced and mature biosimilar markets (e.g., Germany) tend to have more generic-like pricing and reimbursement policies than the less experienced ones (e.g., US). Over time and as physicians, patients and payers get more experience with biosimilars mAbs they will become increasingly accepted and perceived as generics both by physicians and the legislative environment. Although there are some intrinsic differences between biosimilars and generics (such as in their clinical development and manufacturing processes) that will necessitate the continuing need for separate regulatory processes, the concept of biosimilars having distinct market access nuances will gradually be eroded over time.

DISCLAIMER: This article is for educational purposes only. Legal or regulatory advice should be obtained for your specific circumstances.